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Saturday, November 21, 2015

The mass media excitement about Ebola has receded. The 2014-2015 West African outbreak has been brought under
control not thanks to the deployment of successful treatment regimes, because
there are none that are known to work. I participated recently in an
international meeting of experts debating the ethical and methodological issues
pertaining to trial designs for emerging infectious diseases like Ebola. It was
both astounding and also immensely frustrating that to a large extent the controversies
that exercised the minds of the delegates of this meeting exercised the minds
of many an AIDS activist and clinical trials’ expert prior to the advent of
highly active antiretroviral therapy, a good quarter of a century ago.[1][2]Are
placebo controls an ethically defensible methodological tool when patients face
a terminal illness? Different alternative trial designs involving placebo
controls, adaptive trial designs, and multi-stage approaches involving active
controls were discussed during the meeting. The heated nature of some of these
debates reminded me strongly of the passion that was on display during the
early HIV trials. It turns out, despite decades of informed debate about these
issues, a number of significant normative questions have not been settled.

A cluster of difficult ethical questions that engendered justifiably
a lot of debate has to do with the use of placebo controls in trials involving
patients facing a very high mortality risk (some in excess of 90%) and a
fast-acting infection resulting in the death of these patient within 2-8 days
after admission to a treatment centre. This scenario mirrors the sobering reality
faced by a subset of Ebola Virus Disease patients. This issue was already highly
contentious during the early HIV trials, and then patients and clinical
investigators were faced with a virus that was nowhere near as fast-acting as
the Ebola virus. The ethical conflict that arises here is this: We know that
those randomized into the placebo arm face the same greater-than-90%-risk of
death within a few days as those who receive the standard of care treatment. In
some trial design the placebo control arm could be identical to the gold
standard of (unsuccessful) clinical care provided in a particular clinical
setting. Given that those who are randomized into the arm featuring the
unregistered medical intervention might do better, or might do worse,
or might do roughly as badly as those in the placebo control arm, the ethical
question remains whether a trial design featuring a placebo control is
ethically justifiable, given the almost certainty of imminent death faced by
those randomized into the placebo arm. During the meeting I alluded to earlier
a fairly contentious debate arose also over the question of whether trials
producing less reliable results than placebo controlled trials might be
acceptable under such circumstances.

What exacerbates the ethical challenges for those who
undertake such trials is that their trial participants are arguably not true
volunteers. Their – dying - trial participants are not given the opportunity to
choose between participating in the placebo controlled randomized trial versus
accessing the unregistered medical intervention on their own volition outside
the trial process. It is perfectly conceivable that some patients might choose
to participate in such trials in order to facilitate the development of a
successful intervention capable of helping future patients like them. Or they might
accept that there exists true clinical equipoise between the trial arms and
they might be volunteering to be randomized under such circumstances. In the
absence of alternative access routes to the unregistered medical intervention,
we can never be certain that the patients agreeing to be randomized are not
simply responding to what constitutes a coercive offer.

Clinical investigators colluding in this process, and
arguably benefiting from it, are not absolved of their ethical responsibilities
because they did not create the regulatory frameworks that gave rise to the
problem. It is true that they did not create the regulatory framework under
which they operate, but they undoubtedly benefit from its existence. We could
respond to this kind of argument by pointing to the societal need for sound
trial designs and the detrimental impact of permitting patients to access
unregistered medical interventions outside the clinical trials’ system. The
likely impact of permitting patients access, as a senior biostatistician
attending the workshop rightly pointed out to me, would be a significant
slowing-down in the trial recruitment process. Some trials might never be able
to recruit sufficient patients, because most patients might be voting with
their feet and opt to take their chances with the unregistered medical
intervention. Surely that is not quite what is in the best interest of any
society battling an emerging infectious disease such as Ebola. Does this
justify coercing dying people into particular trial designs? I do not think so,
but this is a contentious issue where reasonable, well-informed people can
justifiably differ. A WHO panel looking at this question argued that while it would
be ethically defensible to offer emergency access to unregistered medical interventions
to Ebola patients, this should be subject to that emergency access not slowing
down trial recruitment.[3]
The panelists (not featuring a single expert or disease survivor from the
affected countries) took a policy line here that mirrors US regulations. Other
countries, including Canada and South Africa do not make this a threshold condition
for emergency access. As it is with these sorts of panels, the advice it
rendered on this controversial topic is not actually reasoned for, so policy
makers and regulators as well as patient rights advocates aiming to balance the
competing interests of access versus trial recruitment in a fair manner will be
left wondering about the ethical reasons for this policy stance taken by the
WHO panel, assuming there are any.

There are other ethical issues that arise in this context:
Some experimental agents existed at the time only in insufficient quantities, for
instance ZMapp, an unregistered medical intervention composed of monoclonal
antibodies, was only available in very limited quantities. In light of this
situation, is it acceptable to prioritize patients in comparable clinical
circumstances who are willing to be randomized in a placebo controlled trial
over patients clamoring for direct emergency access, given that the available
quantities of this unregistered medical intervention would have been used up in
the placebo controlled trial?

And here is another difficult question: While the AIDS
activists of days gone by were highly educated about their disease and about
the available unregistered medical interventions considered for expanded access
programs, this is not quite the case with regard to the average West African
Ebola patient. These patients were unlikely
able to provide valid first person informed consent, because they were unable
to demonstrate a reasonable person understanding of what was known about the
unregistered medical intervention, about their options and so on and so forth. This
is the case both because of educational limitations as well as disease
progression. Are short-cuts to informed consent ethically justifiable under
such circumstances? Given that time is of the essence and proxy consent might
not be feasible due to family members being deceased or in a far-away village,
are our informed consent requirements reasonable under such emergency
circumstances?

The WHO panel suggests that evidence from nun-human primate
experiments might be sufficient to justify offering a particular unregistered
medical intervention for emergency access. Is that an ethically justifiable
stance, given the high mortality rate and fast-acting nature of the infection?

Let me leave you with a final difficult question to ponder:
Imagine you were running a medical NGO providing access to unregistered medical
interventions to patients you care for in your emergency medical centre. By some
fluke your unregistered medical intervention permits some of your patients to
survive, but that survival comes at a high price, debilitating after-effects of
the Ebola virus as well as of the unregistered medical intervention. Given
concerns about your patients’ capacity to provide valid informed consent,
should you accept responsibility for the patients’ future care and upkeep,
given the lack of state infrastructure to assist these patients? If you accept
responsibility for their care, say, by taking out an insurance package from
some provider for them, you will expend a fair amount of donor monies on these
patients (potentially for decades) that you cannot use to assist patients also
facing life-threatening illnesses in other parts of the world. In other words,
you face another ethical challenge, a resource allocation challenge. How should
that medical NGO go about addressing this challenge?

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